July 5, 2006
Computer model paves way for virtual screening of treatments for prostate condition

Benign prostatic hyperplasia (BPH) is a common disease in the ageing male population and affects 60% of men over 60. The condition impacts the quality of life of patients and if untreated can lead to serious bladder problems.

There are a variety of treatment options available including surgery and administration of a group of drugs called alpha blockers. However, many of the existing drugs used to treat this condition have unwanted side effects. Research suggests that more selective alpha blockers may have fewer side effects.

Dr Isabel Rozas, from the School of Chemistry, Trinity College Dublin (TCD) and the Centre for Synthesis and Chemical Biology (CSCB), in collaboration with her colleague Dr Graeme Watson (TCD), have recently published work in the Journal of Medicinal Chemistry which improves our understanding of selective alpha blockers and could help researchers design new drug treatments.

"The development of high-affinity or more selective alpha blockers is of paramount importance for the treatment of BPH," explains Dr Rozas.

Alpha blockers, which are known as alpha 1 antagonists, act by relaxing the prostate and bladder smooth muscles improving the flow of urine through the urethra and so helping to relieve the symptoms of BPH. The smooth muscles in the prostate and at the base of the bladder contain different types of receptors called the alpha 1A, 1B and 1D adrenoceptors. These adrenoceptors manage how muscles relax and contract. The alpha 1 blockers bind to all these receptors and cause the muscle to relax.

"A detailed understanding of how these alpha 1 antagonists work has been hampered because little is known about the three-dimensional conformation of the different alpha 1 adrenoceptors," says Dr Rozas. "In our group, we simulate what happens at these receptors using computers with techniques called homology modeling, molecular dynamics (MD) simulations and docking."

The technique of homology modeling is used because it can be very time consuming to establish the three-dimensional conformation of proteins such as the alpha 1 adrenoceptors. With homology modeling, researchers choose as a template a protein with a known three-dimensional conformation which has similar amino acid sequences to the unknown protein. This helps them towards developing a model for the structure of the unknown protein.

"The most thoroughly documented example of a membrane protein is rhodopsin which was first crystallized in its inactive state in 2000 and has been subsequently used as a template for homology modeling of related receptors such as adrenoceptors," says Dr Rozas.

This new research, which was carried out by Dr Gemma Kinsella as part of her PhD thesis at Trinity and funded by IITAC, allowed the chemists to look at a molecular level at what happens when an alpha 1 blocker binds to the alpha 1A adrenoceptor. To test the validity of the model, the chemists screened known alpha 1 antagonists and the results were consistent with previously recorded data.

The results showed that one receptor model is not suitable for screening all antagonists. "It appears necessary to produce an "antagonist-bound" receptor form for each class or family of antagonists to comprehensively evaluate their interactions," explains Dr Rozas.

The advantage of these new models is that they are more flexible than the more rigid rhodopsin-based homology model.

Dr Rozas concludes that "The predicted 3D models could help researchers to design new alpha blockers, for the treatment of BPH, that specifically target the alpha 1A and 1D adrenoceptors, which are located mainly in the prostate and at the base of the bladder respectively, but not the 1B adrenoceptor, which is associated with the unwanted secondary effects."


Publication reference
Kinsella, G. K.; Rozas, I.; Watson, G.W. Computational Study of Antagonist/alpha1A Adrenoceptor Complexes - Observations of Conformational Variations on the Formation of Ligand/Receptor Complexes. J. Med Chem. 2006, 49(2), 501-510.

This article was published in the Clinical section of the Irish Medical Times on July 7 2006.

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